These studies are based on the finding that neuroleptics block the stimulus-coupled release of glutamic acid. This blockade is site-specific (observed only in the amygdala), and independent of dopamine. The specific aims of the proposed experiments are to determine whether this blockade is 1) specific to neuroleptics and 2) due to inhibition of the glutamine-derived or glucose-derived pools of releasable glutamic acid. In studies related to the first specific aim, the effects of antidepressants, anxiolytics, barbituates, amphetamine, and lithium will be evaluated to establish whether they, also, produce this blockade. If they do, then this blockade could not be considered as a potential mechanism for neuroleptic action. Then, a number of neuroleptics not tested previously will be evaluated to assess whether their effects are similar to those produced by haloperidol, chlorpromazine, or clozapine. It would be expected that this blockade of glutamic acid release would be common to all compounds of the neuroleptic class. Third, pairs of active and inactive isomers will be tested to establish whether the blockade is stereospecific. In these cases, only the biologically-active isomer would be expected to be active. The studies related to the second specific aim will involve a comparison of the blockade produced by a specific inhibitor of glutaminase with that produced by neuroleptics to assess whether inhibition of glutamine hydrolysis could be responsible for the neuroleptic-induced blockade. Following this, the relative contributions of glucose and of glutamine to the synthesis of releasable glutamic acid will be established for the synaptosomal preparation employed in these studies. This will be determined by simultaneous C14 and H3 labeling of the glutamine and glucose pools and determining the specific radioactivities of the released glutamic acid. Once these control data have been obtained, the effects of neuroleptics will be determined. Thus, if neuroleptics primarily affect either one pool or the other, it will be demonstrated by this procedure. The long-term objective of this project is to assess whether neuroleptics might act through a glutamatergic mechanism. Before this objective can be approached, however, specificity to neuroleptics and to the readily-released, glutamine-derived pool must be demonstrated. Should a glutamatergic mode of action prove a possibility, it could represent a novel neurochemical approach toward the development of neuroleptics, and possibly further the understanding of the neurochemical basis of schizophrenia.